The present invention provides liquid, semi-solid or solid pharmaceutical formulations that improve the oral bioavailability of hydrophobic pharmaceutical agents, such as indolinone-, quinazoline-, and nitrothiazole-based compounds. Also provided are formulations for parenteral delivery of such hydrophobic pharmaceutical agents, as well as methods of making and using both types of formulations.
The following description of the background of the invention is provided to aid in understanding the invention, but is not admitted to describe or constitute prior art to the invention.
Various methods are available for administering therapeutic agents to a patient. Such methods include, parenteral, oral, ocular, nasal, topical, and transmucosal administration. Variations of these different types of administrations exist. For example, parenteral administration includes intravenous, subcutaneous, intraperitoneal, intramuscular, and intramedullary injection. The chosen mode of administration should take into account the nature of the therapeutic compound and the illness being treated.
Certain potential pharmaceuticals are hydrophobic and typically have very low aqueous solubility and hence low oral bioavailability. Different techniques concerned with solubilizing hydrophobic compounds include those described by Praveen et al., U.S. Pat. No. 5,314,685, and Fernandes et al., U.S. Pat. No. 4,992,271, both of which are incorporated by reference herein in their entirety including any figures and drawings.
One measure of the potential usefulness of an oral formulation of a new pharmaceutical agent is the bioavailability observed after oral administration of the formulation. Various factors can affect the oral bioavailability of the drug. These factors include aqueous solubility, drug absorption throughout the gastrointestinal tract, dosage strength, and first pass effect. Aqueous solubility is one of the most important factors. The oral bioavailability of an aqueous solution formulation of a drug is generally used as the standard or the ideal bioavailability against which other oral formulations are measured. Formulations of drugs that increase the relative bioavailability of the drug as compared to an aqueous solution are desirable, especially with hydrophobic compounds.
The present invention features formulations (including formulations for oral administration as well as parenteral administration) for hydrophobic pharmaceutical agents, such as indolinone-, quinazoline-, or nitrothiazole-based compounds. Such formulations have advantageous solubility characteristics which allow for administration of hydrophobic pharmaceutical agents, such as indolinone-, quinazoline-, or nitrothiazole-based compounds, for pharmaceutical testing and therapy. Not only do such formulations overcome the solubility problems that have previously plagued the art, they have also been shown to produce a therapeutic effect in test animals.
Thus, a first aspect of the present invention features a formulation comprising: (a) one or more hydrophobic pharmaceutical agents, where the agents are independently selected from the group consisting of quinazoline-, nitrothiazole-, and indolinone-based compounds; (b) one or more polyoxyhydrocarbyl compounds; and (c) one or more pharmaceutically acceptable surfactants.
It is anticipated that the one or more hydrophobic pharmaceutical agents may include a combination of nitrothiazole-based compounds with quinazoline-based compounds, or nitrothiazole-based compounds with indolinone-based compounds, or quinazoline-based compounds with indolinone-based compounds. In addition, the one or more hydrophobic pharmaceutical agents may include a combination of indolinone-based compounds, for example 3-[(2,4-dimethylpyrrol-5-yl)methylene]-(5-amino)-2-indolinone, 3-[(2,4-dimethylpyrrol-5-yl)methylene]-(5-chloro)-2-indolinone, 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone, and 3-[(3-methylthiophenyl-5-yl)methylene]-(4-methyl)-2-indolinone. Another possibility is that the one or more hydrophobic pharmaceutical agents may include a combination of quinazoline-based compounds, for example 4-(3-bromophenyl)-6,7-dimethoxyquinazoline and 4-(3-chlorophenyl)-6,7-dimethoxyquinazoline. Or alternatively, the one or more hydrophobic pharmaceutical agents may include a combination of nitrothiazole-based compounds, for example some combination of 2-methyl-5-[(5-nitrothiazol-2-yl)mercapto]-1,3,4-thiadiazole; 1-benzyl-5-[(5-nitrothiazol-2-yl)mercapto]tetrazole; 2-[(5-nitrothiazol-2-yl)mercapto]-5-t-butyl-1,2,4-triazole; 3-[(5-nitrothiazol-2-yl)mercapto]-5-(thien-2-yl)-1,2,4-triazole; 3-[(5-nitrothiazol-2-yl)mercapto]-5-phenyl-1,2,4-triazole; and 4-allyl-3-hydroxy-5-[(5-nitrothiazole-2-yl)mercapto]-1,2,4-triazole.
The term xe2x80x9chydrophobic pharmaceutical agentxe2x80x9d as used herein refers to compounds having a greater solubility in organic solvents of low polarity, such as long chain alcohols, than in aqueous solution. xe2x80x9cHydrophobicxe2x80x9d means xe2x80x9cwater-hatingxe2x80x9d and is used herein to indicate weakly soluble in water and soluble in non-polar solvents. The formulations described by the present invention facilitate solubilization of hydrophobic compounds which readily dissolve in alcohols. Preferably, the hydrophobic compound is A insoluble in aqueous solution. More preferably, the compound has similar solubility characteristics in alcohols and aqueous solution to quinazoline-, nitrothiazole-, and indolinone-based compounds.
The term xe2x80x9ccompoundxe2x80x9d refers to the compound or a pharmaceutically acceptable salt, ester, amide, prodrug, isomer, or metabolite, thereof.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d refers to a formulation of a compound that does not abrogate the biological activity and properties of the compound. Pharmaceutical salts can be obtained by reacting a compound of the invention with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like, or with inorganic or organic bases such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, choline, n-methyl glucamine, diethylamine, procaine and the like.
The term xe2x80x9cprodrugxe2x80x9d refers to an agent that is converted into the parent drug in vivo. Prodrugs may be s easier to administer than the parent drug in some situations. For example, the prodrug may be bioavailable by oral administration but the parent is not, or the prodrug may improve solubility to allow for intravenous administration.
The term xe2x80x9cpolarityxe2x80x9d as used herein refers to the dipole of a molecule. A xe2x80x9cdipolexe2x80x9d is two equal and opposite charges separated in space. A molecule is polar if it has a dipole, i.e. if the center of negative charge does not coincide with the center of positive charge. The dipole moment of a molecule, is equal to the magnitude of the charge multiplied by the distance between the centers of charge. It is possible to measure the dipole moments of molecules by methods well-known in the art. A low dipole moment indicates low polarity.
The term xe2x80x9cquinazoline-based compoundxe2x80x9d refers to a quinazoline organic compound substituted with chemical substituents. Quinazoline compounds are of the general structure: 
The term xe2x80x9csubstitutedxe2x80x9d refers to compounds of the invention that are derivatized with any number of chemical substituents, typically replacing one or more of the hydrogen atoms present in the compound""s general structure.
The term xe2x80x9cnitrothiazole-based compoundxe2x80x9d refers to a nitrothiazole organic compound substituted with chemical substituents. Nitrothiazole compounds are of the general structure: 
The term xe2x80x9cindolinone-based compoundxe2x80x9d refers to a indolinone organic compound substituted with chemical substituents. Indolinone compounds are of the general structure: 
The term xe2x80x9cpolyoxyhydrocarbyl compoundxe2x80x9d as used herein refers to a water soluble carbohydrate such as glucose, sucrose, maltotriose, and the like; water soluble carbohydrate derivatives such as gluconic acid and mannitol, and oligosaccharides; and water soluble polymers such as polyvinylpyrrolidone, poly(vinyl alcohol), and in particular, polyethers such as other polyoxyalkylenes including poly(ethylene glycol), or other water soluble mixed oxyalkylene polymers, and the polymeric form of ethylene glycol. Although polyoxyhydrocarbyl compounds preferably contain more than one carbon, oxygen, and hydrogen atom, some molecules such as poly(ethyleneimine) are also included.
A particularly preferred class of solubilizing polyoxyhydrocarbyl moieties comprises poly(ethylene glycol) (PEG) and PEG derivatives, such as PEG monomethyl ether. Other suitable PEG derivatives include PEG-silicon derived ethers. Many of these polymers are commercially available in a variety of molecular weights. Others may be conveniently prepared from commercially available materials, such as by coupling of amino-PEG moiety to a haloalkyl silyl or silane moiety.
Suitable PEGs may vary in molecular weight from about 200 g/mol to about 20,000 g/mol or more, more preferably 200 g/mol to 5,000 g/mol, even more preferably 250 g/mol to 1,000 g/mol, and most preferably 250 g/mol to 500 g/mol. The choice of a particular molecular weight may depend on the particular hydrophobic pharmaceutical agent chosen and its molecular weight and degree of hydrophobicity, as well as the particular application for which the formulation is to be used.
The term xe2x80x9cpharmaceutically acceptable surfactantxe2x80x9d as used herein refers to a compound that can solubilize hydrophobic compounds into aqueous solutions. Preferably for parenteral formulations, the surfactant is a non-ionic surfactant. Examples of pharmaceutically acceptable surfactants include POLYSORBATE 80(copyright) and other polyoxyethylene sorbitan fatty acid esters, glyceryl monooleate, polyvinyl alcohol, ethylene oxide copolymers such as PLURONIC(trademark) (a polyether) and TETRONIC(trademark) (BASF), polyol moieties, and sorbitan esters. Preferably ethoxylated castor oils, such as CREMOPHOR EL(copyright), are used for the formulation of hydrophobic pharmaceutical agents, such as indolinone-, quinazoline-, and nitrothiazole-based compounds.
The term xe2x80x9cethoxylated castor oilxe2x80x9d as used herein refers to castor oil that is modified with at least one oxygen containing moiety. In particular the term refers to castor oil comprising at least one ethoxyl moiety.
Further, the term xe2x80x9cpharmaceutically acceptable surfactantxe2x80x9d as used herein in reference to oral formulations, includes pharmaceutically acceptable non-ionic surfactants (for example polyoxyethylenepolypropylene glycol, such as POLOXAMER(copyright) 68 (BASF Corp.) or a mono fatty acid ester of polyoxyethylene (20) sorbitan monooleate (TWEEN(copyright) 80), polyoxyethylene (20) sorbitan monostearate (TWEEN(copyright) 60), polyoxyethylene (20) sorbitan monopalmitate (TWEEN(copyright) 40), polyoxyethylene (20) sorbitan monolaurate (TWEEN(copyright) 20) and the like); polyoxyethylene castor oil derivatives (for example, polyoxyethyleneglyceroltriricinoleate or polyoxyl 35 castor oil (CREMOPHOR(copyright) EL, BASF Corp.), polyoxyethyleneglycerol oxystearate (CREMOPHOR(copyright) RH 40 (polyethyleneglycol 40 hydrogenated castor oil) or CREMOPHOR(copyright) RH 60 (polyethyleneglycol 60 hydrogenated castor oil), BASF Corp.) and the like); or a pharmaceutically acceptable anionic surfactant.
The term xe2x80x9cpharmaceutically acceptablexe2x80x9d or xe2x80x9cpharmaceuticalxe2x80x9d as used herein refers to solutions or components of the formulation that do not prevent the therapeutic compound from exerting a therapeutic effect and do not cause unacceptable adverse side effects. Examples of pharmaceutically acceptable reagents are provided in The United States Pharmacopeia The National Formulary, United States Pharmacopeial Convention, Inc., Rockville, Md. 1990 and FDA Inactive Ingredient Guide 1990, 1996 issued by the Division of Drug Information Resources (both are hereby incorporated by reference herein, including any drawings). Unacceptable side effects vary for different diseases. Generally, the more severe the disease the more toxic effects which will be tolerated. Unacceptable side effects for different diseases are known in the art.
In preferred embodiments of the invention, the hydrophobic pharmaceutical agent is a quinazoline-based compound of formula I, 
where R1, R2, R3, R4, R5 and R6 are independently selected from the group consisting of: (i) hydrogen; (ii) saturated or unsaturated alkyl; (iii) an aryl optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro, and ester moieties; (iv) an amine of formula xe2x80x94NX2X3, where X2 and X3 are independently selected from the group consisting of hydrogen, saturated or unsaturated alkyl, and homocyclic or heterocyclic ring moieties; (v) halogen or trihalomethyl; (vi) a ketone of formula xe2x80x94COxe2x80x94X4, where X4 is selected from the group consisting of alkyl and homocyclic or heterocyclic ring moieties; (vii) a carboxylic acid of formula xe2x80x94(X5)nxe2x80x94COOH or ester of formula xe2x80x94(X6)nxe2x80x94COOxe2x80x94X7, where X5, X6, and X7 and are independently selected from the group consisting of alkyl and homocyclic or heterocyclic ring moieties and where n is 0 or 1; (viii) an alcohol of formula (X8)nxe2x80x94OH or an alkoxy moiety of formula xe2x80x94(X8)nxe2x80x94Oxe2x80x94X9, where X8 and X9 are independently selected from the group consisting of saturated or unsaturated alkyl and homocyclic or heterocyclic ring moieties, wherein said ring is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro, and ester and where n is 0 or 1; (ix) an amide of formula xe2x80x94NHCOX10, where X10 is selected from the group consisting of alkyl, hydroxyl, and homocyclic or heterocyclic ring moieties, wherein said ring is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro, and ester; (x) xe2x80x94SO2NX11X12 where X11 and X12 are selected from the group consisting of hydrogen, alkyl, and homocyclic or heterocyclic ring moieties; (xi) a homocyclic or heterocyclic ring moiety optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro, and ester moieties; (xii) an aldehyde of formula xe2x80x94COxe2x80x94H; (xiii) a sulfone of formula xe2x80x94SO2xe2x80x94X13, where X13 is selected from the group consisting of saturated or unsaturated alkyl and homocyclic or heterocyclic ring moieties; and (xiv) a nitro of formula xe2x80x94NO2.
The term xe2x80x9csaturated alkylxe2x80x9d refers to an alkyl moiety that does not contain any alkene or alkyne moieties. The alkyl moiety may be branched or non-branched.
The term xe2x80x9cunsaturated alkylxe2x80x9d refers to an alkyl moiety that contains at least one alkene or alkyne moiety. The alkyl moiety may be branched or non-branched.
The term xe2x80x9carylxe2x80x9d refers to an aromatic group which has at least one ring having a conjugated pi electron system and includes both carbocyclic aryl (e.g. phenyl) and heterocyclic aryl groups (e.g. pyridine). The term xe2x80x9ccarbocyclicxe2x80x9d refers to a compound which contains one or more covalently closed ring structures, and where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from xe2x80x9cheterocyclicxe2x80x9d rings in which the ring backbone contains at least one atom which is different from carbon. The term xe2x80x9cheteroarylxe2x80x9d refers to an aryl group which contains at least one heterocyclic ring.
The term xe2x80x9caminexe2x80x9d refers to a chemical moiety of formula NR1R2 where R1 and R2 are independently selected from the group consisting of hydrogen, saturated or unsaturated alkyl, and homocyclic or heterocyclic ring moieties, where the ring is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, halogen, trihalomethyl, carboxylate, nitro, and ester moieties.
The term xe2x80x9chalogenxe2x80x9d refers to an atom selected from the group consisting of fluorine, chlorine, bromine, and iodine.
The term xe2x80x9cketonexe2x80x9d refers to a chemical moiety with formula xe2x80x94(R)nxe2x80x94COxe2x80x94Rxe2x80x2, where R and Rxe2x80x2 are selected from the group consisting of saturated or unsaturated alkyl and homocyclic or heterocyclic ring moieties and where n is 0 or 1.
The term xe2x80x9ccarboxylic acidxe2x80x9d refers to a chemical moiety with formula xe2x80x94(R)nxe2x80x94COOH, where R is selected from the group consisting of saturated or unsaturated alkyl and homocyclic or heterocyclic ring moieties, and where n is 0 or 1.
The term xe2x80x9calcoholxe2x80x9d refers to a chemical substituent of formula xe2x80x94ROH, where R is selected from the group consisting of saturated or unsaturated alkyl, and homocyclic or heterocyclic ring moieties, where the ring moiety is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, halogen, trihalomethyl, carboxylate, nitro, and ester moieties.
The term xe2x80x9cesterxe2x80x9d refers to a chemical moiety with formula xe2x80x94(R)nxe2x80x94COORxe2x80x2, where R and Rxe2x80x2 are independently selected from the group consisting of saturated or unsaturated alkyl and homocyclic or heterocyclic ring moieties and where n is 0 or 1.
The term xe2x80x9calkoxyxe2x80x9d refers to a chemical substituent of formula xe2x80x94OR, where R is hydrogen or a saturated or unsaturated alkyl moiety.
The term xe2x80x9camidexe2x80x9d refers to a chemical substituent of formula xe2x80x94NHCOR, where R is selected from the group consisting of hydrogen, alkyl, hydroxyl, and homocyclic or heterocyclic ring moieties, where the ring is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, halogen, trihalomethyl, carboxylate, nitro, or ester.
The term xe2x80x9caldehydexe2x80x9d refers to a chemical moiety with formula xe2x80x94(R)nxe2x80x94CHO, where R is selected from the group consisting of saturated or unsaturated alkyl and homocyclic or heterocyclic ring moieties and where n is 0 or 1.
The term xe2x80x9csulfonexe2x80x9d refers to a chemical moiety with formula xe2x80x94SO2xe2x80x94R, where R is selected from the group consisting of saturated or unsaturated alkyl and homocyclic or heterocyclic ring moieties.
In preferred embodiments, the hydrophobic pharmaceutical agent is a quinazoline-based compound of formula II: 
where R1, R2, and R3 are selected from the group consisting of halogen, trihalomethyl, cyano, methoxy, and hydrogen. Most preferably, the quinazoline-based compound is 4-(3-bromophenyl)-6,7-dimethoxyquinazoline.
In other preferred embodiments of the invention, the hydrophobic pharmaceutical agent is a nitrothiazole-based compound of formula III, 
where A represents (i) a substituted or unsubstituted monocyclic five- or six-membered ring having 1 to 4 hetero ring atoms, at least one of which is nitrogen, the remainder of which are selected from the group consisting of nitrogen, oxygen and sulfur, where examples of such rings include, but are not limited to, pyridine, pyrrole, imidazole, thiazole, isothiazole, isoxazole, furazan, pyrrolidine, piperidine, imidazolidine, piperazine, oxazole, tetrazole, pyrazole, triazole, oxadiazole, thiodiazole; (ii) a substituted or unsubstituted monocyclic or fused bicyclic six- to ten-membered ring having 1 to 4 hetero ring atoms, one of which is nitrogen and the remainder of which are selected from the group consisting of nitrogen, oxygen and sulfur, where such rings include, but are not limited to, indole, quinoxaline, quinazoline, quinoline, isoquinoline, purine; or (iii) a substituted or unsubstituted monocyclic or fused polycyclic saturated or unsaturated ring having three to 15 atoms, which are selected from the group consisting of carbon, sulfur, nitrogen and oxygen.
The heterocyclic rings defined above may be saturated or unsaturated. The unsaturated rings or heteroaromatic group may, if desired, bear one or more substituents which do not substantially adversely affect the activity of the compound of formula II. Exemplary of such substituents are alkyl, alkoxy, phenoxy, alkenyl, alkynyl, phenylalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, alkyloxy, alkylthio, alkenylthio, phenylalkylthio, hydroxyalkyl-thio, alkylthiocarbamylthio, phenyl, cyclohexyl, pyridyl, piperidinyl, alkylamino, amino, nitro, mercapto, cyano, hydroxyl, a halogen atom, an oxygen atom (forming a ketone or N-oxide) or a sulphur atom (forming a thione).
The terms xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d as used herein refer to straight or branched chain hydrocarbon groups having from 2 to 10 carbons and unsaturated by a double or triple bond, respectively, such as vinyl, allyl, propargyl, 1-methylvinyl, but-1-enyl, but-2-enyl, but-2-ynyl, 1 methylbut-2-enyl, pent-1-enyl, pent-3-enyl, 3-methylbut-1-ynyl, 1,1-dimethylallyl, hex-2-enyl and 1-methyl-1-ethylallyl.
The term xe2x80x9cphenylalkylxe2x80x9d refers to the aforementioned alkyl groups substituted by a phenyl group. Examples of phenylalkyl groups include, but are not limited to, benzyl, phenethyl, phenopropyl, 1-benzylethyl, phenobutyl and 2-benzylpropyl. The term xe2x80x9chydroxy-alkylxe2x80x9d refers to the aforementioned alkyl groups substituted by a single hydroxyl group. Examples of hydroxyalkyl goups include, but are not limited to, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, 1-hydroxybutyl and 6-hydroxyhexyl.
The terms xe2x80x9calkylthio, alkenylthio, alkynylthio, alkylthio, hydroxy-alkylthio and phenyl-alkylthioxe2x80x9d as used herein refer to the aforementioned alkyl, alkenyl, alkynyl, hydroxy-alkyl and phenyl-alkyl groups linked through a sulfur atom to the compounds of the present invention.
In yet other preferred embodiments, the hydrophobic pharmaceutical agent is a nitrothiazole-based compound of formula IV: 
where R1, R2, and R3 are independently selected from the group consisting of: (i) hydrogen; (ii) saturated or unsaturated alkyl; (iii) an aryl optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro, and ester moieties; (iv) an amine of formula xe2x80x94NX2X3, where X2 and X3 are independently selected from the group consisting of hydrogen, saturated or unsaturated alkyl, and homocyclic or heterocyclic ring moieties; (v) halogen or trihalomethyl; (vi) a ketone of formula xe2x80x94COxe2x80x94X4, where X4 is selected from the group consisting of alkyl and homocyclic or heterocyclic ring moieties; (vii) a carboxylic acid of formula xe2x80x94(X5)nxe2x80x94COOH or ester of formula xe2x80x94(X6)nxe2x80x94COOxe2x80x94X7, where X5, X6, and X7 and are independently selected from the group consisting of alkyl and homocyclic or heterocyclic ring moieties and where n is 0 or 1; (viii) an alcohol of formula (X8)nxe2x80x94OH or an alkoxy moiety of formula xe2x80x94(X8)nxe2x80x94Oxe2x80x94X9, where X8 and X9 are independently selected from the group consisting of saturated or unsaturated alkyl and homocyclic or heterocyclic ring moieties, wherein said ring is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro, and ester and where n is 0 or 1; (ix) an amide of formula xe2x80x94NHCOX10, where X10 is selected from the group consisting of alkyl, hydroxyl, and homocyclic or heterocyclic ring moieties, wherein said ring is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro, and ester; (x) xe2x80x94SO2NX11X12, where X11 and X12 are selected from the group consisting of hydrogen, alkyl, and homocyclic or heterocyclic ring moieties; (xi) a homocyclic or heterocyclic ring moiety optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro, and ester moieties; (xii) an aldehyde of formula xe2x80x94COxe2x80x94H; (xiii) a sulfone of formula xe2x80x94SO2xe2x80x94X13, where X13 is selected from the group consisting of saturated or unsaturated alkyl and homocyclic or heterocyclic ring a moieties; and (xiv) a nitro of formula xe2x80x94NO2.
In yet other preferred embodiments of the invention, the hydrophobic pharmaceutical agent is a nitrothiazole-based compound of formula V: 
or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are independently selected from the group consisting of: (i) hydrogen; (ii) saturated or unsaturated alkyl; (iii) an aryl optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro, and ester moieties; (iv) an amine of formula xe2x80x94NX2X3, where X2 and X3 are independently selected from the group consisting of hydrogen, saturated or unsaturated alkyl, and homocyclic or heterocyclic ring moieties; (v) halogen or trihalomethyl; (vi) a ketone of formula xe2x80x94COxe2x80x94X4, where X4 is selected from the group consisting of alkyl and homocyclic or heterocyclic ring moieties; (vii) a carboxylic acid of formula xe2x80x94(X5)nxe2x80x94COOH or ester of formula xe2x80x94(X6)nxe2x80x94COOxe2x80x94X7, where X5, X6, and X7 and are independently selected from the group consisting of alkyl and homocyclic or heterocyclic ring moieties and where n is 0 or 1; (viii) an alcohol of formula (X8)nxe2x80x94OH or an alkoxy moiety of formula xe2x80x94(X8)nxe2x80x94Oxe2x80x94X9, where X8 and X9 are independently selected from the group consisting of saturated or unsaturated alkyl and homocyclic or heterocyclic ring moieties, wherein said ring is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro, and ester and where n is 0 or 1; (ix) an amide of formula xe2x80x94NHCOX10, where X10 is selected from the group consisting of alkyl, hydroxyl, and homocyclic or heterocyclic ring moieties, wherein said ring is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro, and ester; (x) xe2x80x94SO2NX11X12, where X11 and X12 are selected from the group consisting of hydrogen, alkyl, and homocyclic or heterocyclic ring moieties; (xi) a homocyclic or heterocyclic ring moiety optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro, and ester moieties; (xii) an aldehyde of formula xe2x80x94COxe2x80x94H; (xiii) a sulfone of formula xe2x80x94SO2xe2x80x94X13, where X13 is selected from the group consisting of saturated or unsaturated alkyl and homocyclic or heterocyclic ring moieties; and (xiv) a nitro of formula xe2x80x94NO2.
In particularly preferred embodiments, the nitrothiazole-based compound is selected from the group consisting of: 2-methyl-5-[(5-nitrothiazol-2-yl)mercapto]-1,3,4-thiadiazole; 1-benzyl-5-[(5-nitrothiazol-2-yl)mercapto]tetrazole; 2-[(5-nitrothiazol-2-yl)mercapto]-5-t-butyl-1,2,4-triazole; 3-[(5-nitrothiazol-2-yl)mercapto]-5-(thien-2-yl)-1,2,4-triazole; 3-[(5-nitrothiazol-2-yl)mercapto]-5-phenyl-1,2,4-triazole; and 4-allyl-3-hydroxy-5-[(5-nitrothiazole-2-yl)mercapto]-1,2,4-triazole.
In yet other preferred embodiments of the invention, the hydrophobic pharmaceutical agent is a indolinone-based compound of formula VI: 
where R1, R2, R3, and R4 are selected from the group
consisting of hydrogen, trihalomethyl, hydroxyl,
amine, thioether, cyano, alkoxy, alkyl, amino, bromo,
fluoro, chloro, iodo, mercapto, thio, cyanoamido,
alkylthio, aryl, heteroaryl, carboxyl, ester, oxo,
alkoxycarbonyl, alkenyl, alkoxy, nitro, alkoxyl, and
amido moieties; and R5 is an optionally substituted aryl
or heteroaryl cyclic moiety.
Preferably, the indolinone-based compound has a structure of formula VI, where R1, R2, R3, and R4 are selected from the group consisting of hydrogen, halogen, alkyl, and alkoxy; and where R5 is a pyrrolyl or thiophenyl moiety optionally substituted with moieties selected from the group consisting of hydrogen, halogen, alkyl, and alkoxy.
More preferably, the indolinone-based compound is selected from the group consisting of 3-[(2,4-dimethylpyrrol-5-yl)methylene]-(5-amino)-2-indolinone, 3-[(2,4-dimethylpyrrol-5-yl)methylene]-(5-chloro)-2-indolinone, 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone, and 3-[(3-methylthiophenyl-5-yl)methylene]-(4-methyl)-2-indolinone. Most preferably, the indolinone-based compound is 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone.
In some embodiments of the invention, the one or more polyoxyhydrocarbyl compounds are independently selected from the group consisting of: water soluble carbohydrates, water soluble carbohydrate derivatives, polypeptides, water soluble polymers, water soluble mixed oxyalkylene polymers, and the polymeric form of ethylene glycol. Preferably, the one or more polyoxyhydrocarbyl compounds are poly(ethylene glycol) (PEG) or PEG derivatives. More preferably, PEG may vary in molecular weight from about 200 daltons to about 20,000 daltons.
In other embodiments of the invention, the one or more surfactants are one or more non-ionic surfactants. Preferably, the one or more surfactants are independently selected from the group consisting of: polyoxyethylene sorbitan fatty acid esters, glyceryl monooleate, polyvinyl alcohol, ethylene oxide copolymers, polyol moieties, and sorbitan esters. More preferably, the one or more surfactants are one or more ethoxylated castor oils. Most preferably, the ethoxylated castor oil is CREMOPHOR EL(copyright).
In preferred embodiments of the invention the formulation also includes one or more pharmaceutically acceptable alcohols. Preferably, the one or more alcohols are independently selected from the group consisting of ethanol, benzyl alcohol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, and glycerol. Most preferably, the alcohols are ethanol and benzyl alcohol.
The term xe2x80x9cpharmaceutically acceptable alcoholxe2x80x9d as used herein refers to alcohols which are liquids at about room temperature (approximately 20xc2x0 C.). These include propylene glycol, ethanol, 2-(2-ethoxyethoxy)ethanol (TRANSCUTOL(copyright), Gattefosse, Westwood, N.J. 07675), benzyl alcohol, and glycerol.
The formulation should be dissolved in a sufficient amount of a pharmaceutically acceptable aqueous solution prior to patient administration to avoid toxic effects due to the alcohol content. The added amount of a pharmaceutically acceptable aqueous solution should be sufficient to avoid hemolysis. Examples of suitable pharmaceutically acceptable aqueous solutions such as WFI (water for injection) and solutions containing isotonic saline are known in the art. Pharmaceutically acceptable aqueous solutions include 0.45% N saline, WFI (water for injection), D5W (5% dextrose in water), and D5W 0.45% N saline.
In other embodiments of the invention, when the hydrophobic pharmaceutical agent is an indolinone-based compound substituted with one or more carboxyl moieties, the formulation further comprises water.
In preferred embodiments of the invention, the formulation comprises (a) 0.1 to 100 mg/mL of an indolinone-based compound of formula VI, where R1, R2, R3, and R4 are selected from the group consisting of hydrogen, trihalomethyl, hydroxyl, amine, thioether, cyano, alkoxy, alkyl, amino, bromo, fluoro, chloro, iodo, mercapto, thio, cyanoamido, alkylthio, aryl, heteroaryl, carboxyl, ester, oxo, alkoxycarbonyl, alkenyl, alkoxy, nitro, alkoxyl, and amido moieties; and R5 is an optionally substituted aryl or heteroaryl cyclic moiety; (b) 0.01 to 10 g/mL PEG-400; (c) 0.01 to 1 g/mL ethanol; (d) 0.001 to 1 g/mL benzyl alcohol; and (e) 0.01 to 10 g/mL ethoxylated castor oil.
The term xe2x80x9cPEG-400xe2x80x9d as used herein refers to a polymeric form of ethylene glycol, polyethylene glycol (PEG), which has an average molecular weight of 400 grams/mole.
In other preferred embodiments the formulation comprises (a) about 5.0 mg/mL of an indolinone-based compound of formula VI, where R1, R2, R3, and R4 are selected from the group consisting of hydrogen, trihalomethyl, hydroxyl, amine, thioether, cyano, alkoxy, alkyl, amino, bromo, fluoro, chloro, iodo, mercapto, thio, cyanoamido, alkylthio, aryl, heteroaryl, carboxyl, ester, oxo, alkoxycarbonyl, alkenyl, alkoxy, nitro, alkoxyl, and amido moieties; and R5 is an optionally substituted aryl or heteroaryl cyclic moiety; (b) about 0.35 g/mL PEG-400 (c) about 0.114 g/mL ethanol; (d) about 0.02 g/mL benzyl alcohol; and (e) about 0.25 g/mL CREMOPHOR EL(copyright).
In other preferred embodiments, the invention relates to formulations comprising an indolinone-based compound of formula VI, where R1, R2, R3, and R4 are selected from the group consisting of hydrogen, halogen, alkyl, and alkoxy; and where R5 is a pyrrolyl or thiophenyl moiety optionally substituted with moieties selected from the group consisting of hydrogen, halogen, alkyl, and alkoxy.
In still other preferred embodiments, the invention relates to formulations comprising an indolinone-based compound selected from the group consisting of 3-[(2,4-dimethylpyrrol-5-yl)methylene]-(5-amino)-2-indolinone, 3-[(2,4-dimethylpyrrol-5-yl)methylene]-(5-chloro)-2-indolinone, 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone, and 3-[(3-methylthiophenyl-5-yl)methylene]-(4-methyl)-2-indolinone.
A highly preferred embodiment of the invention relates to a formulation comprising about 4.5 mg/mL of the indolinone-based compound, 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone, (b) about 45% w/v PEG-400, (c) about 31.5% w/v CREMOPHOR EL(copyright), (d) about 2% w/v benzyl alcohol, and (e) about 9.5% w/v ethanol.
The formulations are stated to comprise the elements described herein, meaning that the formulations can include other components. The solution containing the hydrophobic pharmaceutical agents is preferably adjusted to a pH where the compounds are stable. The pH is preferably adjusted to between 2 and 7. The pH can be adjusted using pharmaceutically acceptable excipients such as ascorbic acid, citric acid, lactic acid, acetic acid, tartaric acid, sodium sulfate, hydrochloric acid, sodium hydroxide, sodium phosphate and sodium acetate. Glycerine can also be added, typically to adjust the isotonicity of a parenteral formulation.
Other components can also be added to the formulations to enhance the therapeutic effects. For example, the hydrophobic pharmaceutical agents may be further formulated in liposomes in addition to the above-mentioned components. Liposomes have been shown to enhance the delivery of compounds into cells by enhancing the compounds"" ability to pass through cell plasma membranes to the interior of the cells. However, because the formulations have been shown to have a therapeutic effect with only the components described herein, formulations of the present invention may also xe2x80x9cconsist essentially ofxe2x80x9d or xe2x80x9cconsist ofxe2x80x9d these components.
In preferred embodiments of the invention, the formulations are effective in treating or preventing an abnormal condition in a patient in need of such treatment. The patient is preferably a mammal and more preferably a human. In a highly preferred embodiment, the formulations are parenteral. Parenteral administration includes intravenous, subcutaneous, intraperitoneal, intramuscular and intramedullary injection.
The term xe2x80x9cpreventingxe2x80x9d as used herein refers to administering the formulation to a patient before the abnormal condition manifests itself in that patient.
The term xe2x80x9ctreatingxe2x80x9d as used herein refers to the method of the invention having a therapeutic effect and at least partially alleviating or abrogating the abnormal condition in the organism.
The term xe2x80x9ctherapeutic effectxe2x80x9d as used herein refers to the inhibition of cell growth causing or contributing to an abnormal condition. The term xe2x80x9ctherapeutic effectxe2x80x9d also refers to the inhibition of factors causing or contributing to the abnormal condition. A therapeutic effect relieves to some extent one or more of the symptoms of the abnormal condition.
The term xe2x80x9cmammalxe2x80x9d as used herein preferably refers to such organisms as mice, rats, rabbits, guinea pigs, goats, sheep, horses, and cows, for example; more preferably to dogs, cats, monkeys, and apes; and most preferably to humans.
The term xe2x80x9ccell proliferative disorderxe2x80x9d as used herein refers to a disorder where an excess cell proliferation of one or more subset of cells in a multicellular organism occurs resulting in harm (e.g., discomfort or decreased life expectancy) to the multicellular organism. The excess cell proliferation can be determined by reference to the general population and/or by reference to a particular patient (e.g., at an earlier point in the patient""s life). Hyper-proliferative cell disorders can occur in different types of animals and in humans, and produce different physical manifestations depending upon the affected cells. Hyper-proliferative cell disorders include cancers, blood vessel proliferative disorders, fibrotic disorders, and autoimmune disorders.
In reference to the treatment of abnormal cell proliferative conditions, a therapeutic effect refers to one or more of the following: (a) a reduction in tumor size; (b) inhibition (i.e., slowing or stopping) tumor metastasis; (c) inhibition of tumor growth; and (d) relieving to some extent one or more of the symptoms associated with the abnormal condition. Compounds demonstrating efficacy against leukemias can be identified as described herein, except that rather than inhibiting metastasis, the compounds may instead slow or decrease cell proliferation or cell growth.
The term xe2x80x9cabnormal conditionxe2x80x9d refers to a function in the cells or tissues of a patient that deviates from their normal functions in that patient. An abnormal condition can relate to cell proliferation as described herein.
The present invention also features oral formulations for hydrophobic pharmaceutical agents, such as quinazoline-, nitrothiazole- and indolinone-based compounds. The oral formulations, which include one or more polyoxyhydrocarbyl compounds, one or more polyglycolized lipids, and one or more surfactants, also have advantageous solubility characteristics and oral bioavailability. These formulations allow for the oral administration of the hydrophobic pharmaceutical agents for testing and therapy and have shown efficacy in the preclinical angiogenesis mice model. 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone is the most widely tested of Applicant""s indolinone-based compounds. The oral formulations of 3-[(2,4-dimethylpyrrol-5-yl)methylenel-2-indolinone have shown therapeutic effect in-test animals.
Thus, a featured aspect of the invention is a formulation comprising: (a) one or more hydrophobic pharmaceutical agents, where the agents are independently selected from the group consisting of quinazoline-, nitrothiazole- and indolinone-based compounds; (b) one or more polyoxyhydrocarbyl compounds; (c) one or more polyglycolized lipids; and (d) one or more pharmaceutically acceptable surfactants.
It is anticipated that the one or more hydrophobic pharmaceutical agents may include a combination of nitrothiazole-based compounds with quinazoline-based compounds, or nitrothiazole-based compounds with indolinone-based compounds, or quinazoline-based compounds with indolinone-based compounds. In addition, the one or more hydrophobic pharmaceutical agents may include a combination of indolinone-based compounds, for example 3-[(2,4-dimethylpyrrol-5-yl)methylene]-(5-amino)-2-indolinone, 3-[(2,4-dimethylpyrrol-5-yl)methylene]-(5-chloro)-2-indolinone, 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone, and 3-[(3-methylthiophenyl-5-yl)methylene]-(4-methyl)-2-indolinone. Another possiblity is that the one or more hydrophobic pharmaceutical agents may include a combination of quinazoline-based compounds, for example 4-(3-bromophenyl)-6,7-dimethoxyquinazoline and 4-(3-chlorophenyl)-6,7-dimethoxyquinazoline. Or alternatively, the one or more hydrophobic pharmaceutical agents may include a combination of nitrothiazole-based compounds, for example some combination of 2-methyl-5-[(5-nitrothiazol-2-yl)mercapto]-1,3,4-thiadiazole; 1-benzyl-5-[(5-nitrothiazol-2-yl)mercapto]tetrazole; 2-[(5-nitrothiazol-2-yl)mercapto]-5-t-butyl-1,2,4-triazole; 3-[(5-nitrothiazol-2-yl)mercapto]-5-(thien-2-yl)-1,2,4-triazole; 3-(5-nitrothiazol-2-yl)mercapto]-5-phenyl-1,2,4-triazole; and 4-allyl-3-hydroxy-5-[(5-nitrothiazole-2-yl)mercapto]-1,2,4-triazole.
The term xe2x80x9cpolyglycolized lipidsxe2x80x9d as used herein refers to mixtures of monoglycerides, diglycerides, or triglycerides and polyethyleneglycol monoesters and diesters formed by the partial alcoholysis of vegetable oil using PEG of 200 g/mol to 2,000 g/mol or by the esterification of fatty acids using PEG 200 g/mol to 2,000 g/mol and glycerols. Preferably these include GELUCIRE(copyright) 35/10, GELUCIRE(copyright) 44/14, GELUCIRE(copyright) 46/07, GELUCIRE(copyright) 50/13, GELUCIRE(copyright) 53/10, and LABRASOL(copyright).
In preferred embodiments of the invention, the hydrophobic pharmaceutical agent is a quinazoline-based compound of formula I, where R1, R2, R3, R4, R5 and R6 are independently selected from the group consisting of: (i) hydrogen; (ii) saturated or unsaturated alkyl; (iii) an aryl optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro, and ester moieties; (iv) an amine of formula xe2x80x94NX2X3, where X2 and X3 are independently selected from the group consisting of hydrogen, saturated or unsaturated alkyl, and homocyclic or heterocyclic ring moieties; (v) halogen or trihalomethyl; (vi) a ketone of formula xe2x80x94COxe2x80x94X4, where X4 is selected from the group consisting of alkyl and homocyclic or heterocyclic ring moieties; (vii) a carboxylic acid of formula xe2x80x94(X5)nxe2x80x94COOH or ester of formula xe2x80x94(X6)nxe2x80x94COOxe2x80x94X7, where X5, X6, and X7 and are independently selected from the group consisting of alkyl and homocyclic or heterocyclic ring moieties and where n is 0 or 1; (viii) an alcohol of formula (X8)nxe2x80x94OH or an alkoxy moiety of formula xe2x80x94(X8)nxe2x80x94Oxe2x80x94X9, where X8 and X9 are independently selected from the group consisting of saturated or unsaturated alkyl and homocyclic or heterocyclic ring moieties, wherein said ring is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxy; halogen, trihalomethyl, carboxylate, nitro, and ester and where n is 0 or 1; (ix) an amide of formula xe2x80x94NHCOX10, where X10 is selected from the group consisting of alkyl, hydroxyl, and homocyclic or heterocyclic ring moieties, wherein said ring is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro, and ester; (x) xe2x80x94SO2NX11X12, where X11 and X12 are selected from the group consisting of hydrogen, alkyl, and homocyclic or heterocyclic ring moieties; (xi) a homocyclic or heterocyclic ring moiety optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro, and ester moieties; (xii) an aldehyde of formula xe2x80x94COxe2x80x94H; and (xiii) a sulfone of formula xe2x80x94SO2xe2x80x94X13, where X13 is selected from the group consisting of saturated or unsaturated alkyl and homocyclic or heterocyclic ring moieties.
In other preferred embodiments of the invention, the hydrophobic pharmaceutical agent is a quinazoline-based compound of formula II, where R1, R2, and R3 are selected from the group consisting of halogen, trihalomethyl, cyano, methoxy, and hydrogen. Most preferably, the quinazoline-based compound is 4-(3-bromophenyl)-6,7-dimethoxyquinazoline.
In yet other preferred embodiments of the invention, the hydrophobic pharmaceutical agent is a nitrothiazole-based compound of formula IV, wherein R1, R2, and R3 are independently selected from the group consisting of: (i) hydrogen; (ii) saturated or unsaturated alkyl; (iii) an aryl optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro, and ester moieties; (iv) an amine of formula xe2x80x94NX2X3, where X2 and X3 are independently selected from the group consisting of hydrogen, saturated or unsaturated alkyl, and homocyclic or heterocyclic ring moieties; (v) halogen or trihalomethyl; (vi) a ketone of formula xe2x80x94COxe2x80x94X4, where X4 is selected from the group consisting of alkyl and homocyclic or heterocyclic ring moieties; (vii) a carboxylic acid of formula xe2x80x94(X5)nxe2x80x94COOH or ester of formula xe2x80x94(X6)nxe2x80x94COOxe2x80x94X7, where X5, X6, and X7 and are independently selected from the group consisting of alkyl and homocyclic or heterocyclic ring moieties and where n is 0 or 1; (viii) an alcohol of formula (X8)nxe2x80x94OH or an alkoxy moiety of formula xe2x80x94(X8)nxe2x80x94Oxe2x80x94X9, where X8 and X9 are independently selected from the group consisting of saturated or unsaturated alkyl and homocyclic or heterocyclic ring moieties, wherein said ring is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro, and ester and where n is 0 or 1; (ix) an amide of formula xe2x80x94NHCOX10, where X10 is selected from the group consisting of alkyl, hydroxyl, and homocyclic or heterocyclic ring moieties, wherein said ring is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro, and ester; (x) xe2x80x94SO2NX11X12, where X11 and X12 are selected from the group consisting of hydrogen, alkyl, and homocyclic or heterocyclic ring moieties; (xi) a homocyclic or heterocyclic ring moiety optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro, and ester moieties; (xii) an aldehyde of formula xe2x80x94COxe2x80x94H; and (xiii) a sulfone of formula xe2x80x94SO2xe2x80x94X13, where X13 is selected from the group consisting of saturated or unsaturated alkyl and homocyclic or heterocyclic ring moieties.
In yet other preferred embodiments of the invention, the hydrophobic pharmaceutical agent is a nitrothiazole-based compound of formula V, wherein R1 and R2 are independently selected from the group consisting of: (i) hydrogen; (ii) saturated or unsaturated alkyl; (iii) an aryl optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro, and ester moieties; (iv) an amine of formula xe2x80x94NX2X3, where X2 and X3 are independently selected from the group consisting of hydrogen, saturated or unsaturated alkyl, and homocyclic or heterocyclic ring moieties; (v) halogen or trihalomethyl; (vi) a ketone of formula xe2x80x94COxe2x80x94X4, where X4 is selected from the group consisting of alkyl and homocyclic or heterocyclic ring moieties; (vii) a carboxylic acid of formula xe2x80x94(X5)nxe2x80x94COOH or ester of formula xe2x80x94(X6)nxe2x80x94COOxe2x80x94X7, where X5, X6, and X7 and are independently selected from the group consisting of alkyl and homocyclic or heterocyclic ring moieties and where n is 0 or 1; (viii) an alcohol of formula (X8)nxe2x80x94OH or an alkoxy moiety of formula xe2x80x94(X8)nxe2x80x94Oxe2x80x94X9, where X8 and X9 are independently selected from the group consisting of saturated or unsaturated alkyl and homocyclic or heterocyclic ring moieties, wherein said ring is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro, and ester and where n is 0 or 1; (ix) an amide of formula xe2x80x94NHCOX10 where X10 is selected from the group consisting of alkyl, hydroxyl, and homocyclic or heterocyclic ring moieties, wherein said ring is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro, and ester; (x) xe2x80x94SO2NX11X12, where X11 and X12 are selected from the group consisting of hydrogen, alkyl, and homocyclic or heterocyclic ring moieties; (xi) a homocyclic or heterocyclic ring moiety optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro, and ester moieties; (xii) an aldehyde of formula xe2x80x94COxe2x80x94H; and (xiii) a sulfone of formula xe2x80x94SO2xe2x80x94X13, where X13 is selected from the group consisting of saturated or unsaturated alkyl and homocyclic or heterocyclic ring moieties.
In particularly preferred embodiments of the invention, the nitrothiazole-based compound is selected from the group consisting of: 2-methyl-5-[(5-nitrothiazol-2-yl)mercapto]-1,3,4-thiadole; 1-benzyl-5-[(5-nitrothiazol-2-yl)mercapto]tetrazole; 2-[(5-nitrothiazol-2-yl)mercapto]-5-t-butyl-1,2,4-triazole; 3-[(5-nitrothiazol-2-yl)mercapto]-5-(thien-2-yl)-1,2,4-triazole; 3-[(5-nitrothiazol-2-yl)mercapto]-5-phenyl-1,2,4-triazole; and 4-allyl-3-hydroxy-5-[(5-nitrothiazole-2-yl)mercapto]-1,2,4-triazole.
In other preferred embodiments of the invention, the hydrophobic pharmaceutical agent is an indolinone-based compound of formula VI, where R1, R2, R3, and R4 are selected from the group consisting of hydrogen, trihalomethyl, hydroxyl, amine, thioether, cyano, alkoxy, alkyl, amino, bromo, fluoro, chloro, iodo, mercapto, thio, cyanoamido, alkylthio, aryl, heteroaryl, carboxyl, ester, oxo, alkoxycarbonyl, alkenyl, alkoxy, nitro, alkoxyl, and amido moieties; and R5 is an optionally substituted aryl or heteroaryl cyclic moiety.
Preferably, the indolinone-based compound has a structure of formula VI, where R1, R2, R3, and R4 are selected from the group consisting of hydrogen, halogen, alkyl, and alkoxy; and where R5 is a pyrrolyl or thiophenyl moiety optionally substituted with moieties selected from the group consisting of hydrogen, halogen, alkyl, and alkoxy.
More preferably, the indolinone-based compound is selected from the group consisting of 3-[(2,4-dimethylpyrrol-5-yl)methylene]-(5-amino)-2-indolinone, 3-[(2,4-dimethylpyrrol-5-yl)methylene]-(5-chloro)-2-indolinone, 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone, and 3-[(3-methylthiophenyl-5-yl)methylene]-(4-methyl)-2-indolinone. Most preferably, the indolinone-based compound is 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone.
In some embodiments of the invention, the one or more polyoxyhydrocarbyl compounds are independently selected from the group consisting of: water soluble carbohydrates, water soluble carbohydrate derivatives, polypeptides, water soluble polymers, water soluble mixed oxyalkylene polymers, and the polymeric form of ethylene glycol. Preferably, the one or more polyoxyhydrocarbyl compounds are poly(ethylene glycol) (PEG) or PEG derivatives. More preferably, PEG may vary in molecular weight from about 200 daltons to about 20,000 daltons.
In other embodiments of the invention, the one or more polyglycolized lipids are mixtures of monoglycerides, diglycerides, or triglycerides and polyethyleneglycol monoesters and diesters. Preferably, the one or more polyglycolized lipids are selected from the group consisting of: GELUCIRE(copyright) 35/10, GELUCIRE(copyright) 44/14, GELUCIRE(copyright) 46/07, GELUCIRE(copyright) 50/13, GELUCIRE(copyright) 53/10, and LABRASOL(copyright). Most preferably, the polyglycolized lipids are selected from the group consisting of GELUCIRE(copyright) 44/14 and LABRASOL(copyright).
In other embodiments of the invention, the one or more surfactants are selected independently from the group consisting of pharmaceutically acceptable non-ionic surfactants, polyoxyethylene castor oil derivatives, and pharmaceutically acceptable anionic surfactants. In highly preferred embodiments, the surfactant is CREMOPHOR EL(copyright).
Other preferred embodiments of the invention feature formulations that also contain one or more pharmaceutically acceptable oils selected independently from the group consisting of mineral oil, vegetable oil, fractionated coconut oil, propyleneglycol monolaurate, and mixed triglycerides with caprylic acid and capric acid. In a highly preferred embodiment, the oil is Miglyol 812.
The term xe2x80x9cpharmaceutically acceptable oilsxe2x80x9d as used herein refers to oils such as mineral oil or vegetable oil (including safflower oil, peanut oil, and olive oil), fractionated coconut oil, propyleneglycol monolaurate, mixed triglycerides with caprylic acid and capric acid, and the like. Preferred embodiments of the invention feature mineral oil, vegetable oil, fractionated coconut oil, mixed triglycerides with caprylic acid, and capric acid. A highly preferred embodiment of the invention features Miglyol 812 (available from Huls America, USA).
In yet other preferred embodiments, when the hydrophobic pharmaceutical agent is an indolinone-based compound substituted with one or more carboxyl moieties, the formulation also comprises water.
In other preferred embodiments, the invention relates to formulations comprising: (a) about 3% w/w of is an indolinone-based compound of formula VI, where R1, R2, R3, and R4 are selected from the group consisting of hydrogen, trihalomethyl, hydroxyl, amine, thioether, cyano, alkoxy, alkyl, amino, bromo, fluoro, chloro, iodo, mercapto, thio, cyanoamido, alkylthio, aryl, heteroaryl, carboxyl, ester, oxo, alkoxycarbonyl, alkenyl, alkoxy, nitro, alkoxyl, and amido moieties; and R5 is an optionally substituted aryl or heteroaryl cyclic moiety; (b) about 70% w/w GELUCIRE(copyright) 44/14; (c) about 10% w/w CREMOPHOR EL(copyright); (d) about 10% w/w Miglyol 812; and (e) about 10% w/w polyethylene glycol 600.
In other preferred embodiments, the invention relates to formulations comprising: (a) about 3% w/w of an indolinone-based compound of formula VI, where R1, R2, R3, and R4 are selected from the group consisting of hydrogen, trihalomethyl, hydroxyl, amine, thioether, cyano, alkoxy, alkyl, amino, bromo, fluoro, chloro, iodo, mercapto, thio, cyanoamido, alkylthio, aryl, heteroaryl, carboxyl, ester, oxo, alkoxycarbonyl, alkenyl, alkoxy, nitro, alkoxyl, and amido moieties; and R5 is an optionally substituted aryl or heteroaryl cyclic moiety; (b) about 76% w/w LABRASOL(copyright); (c) about 12% w/w CREMOPHOR EL(copyright); and (d) about 12% w/w polyethylene glycol 600.
In other preferred embodiments, the invention relates to formulations comprising: (a) about 3% w/w of an indolinone-based compound of formula VI, where R1, R2, R3, and R4 are selected from the group consisting of hydrogen, trihalomethyl, hydroxyl, amine, thioether, cyano, alkoxy, alkyl, amino, bromo, fluoro, chloro, iodo, mercapto, thio, cyanoamido, alkylthio, aryl, heteroaryl, carboxyl, ester, oxo, alkoxycarbonyl, alkenyl, alkoxy, nitro, alkoxyl, and amido moieties; and R5 is an optionally substituted aryl or heteroaryl cyclic moiety; (b) about 70% w/w LABRASOL(copyright); (c) about 10% w/w CREMOPHOR EL(copyright); (d) about 10% w/w Miglyol 812; and (e) about 10% w/w polyethylene glycol 600.
In the most preferred embodiments, these formulations feature 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone as the indolinone-based compound.
Preferably, the formulations are effective in treating or preventing an abnormal condition in a patient, preferably a mammal, more preferably a human, in need of such treatment. The formulation is preferably administered orally. Abnormal conditions which may be treated with these formulations include cell proliferative disorders, typically those characterized by abnormal protein kinase activity. Preferably, the formulation inhibits protein kinase activity.
The compositions of the invention can also include from about 0 to about 3 molar equivalents (based on the amount of the indolinone-based compound or other hydrophobic pharmaceutical agent in the composition) of a pharmaceutically acceptable acid or base or a mixture of pharmaceutically acceptable acids or bases. Preferably, the pharmaceutically acceptable acid or base or mixture of pharmaceutically acceptable acids is present in a total amount of from about 0.2 to about 2.0 molar equivalents (based on the amount of the indolinone-based compound or other hydrophobic pharmaceutical agent in the composition).
The solution can also include from about 0% to about 10% (by weight of the total solution) of water, and may also include an antioxidant (for example, ascorbic acid, BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene), vitamin E, vitamin E PEG 1000 succinate and the like) for chemical stability. Solutions encapsulated in a SEC may also include glycerin for physical stability.
The compositions of this invention (e.g. solution/semisolid or solid or encapsulated solution/semisolid or solid) provide improved oral bioavailability for 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone when compared to non-formulated 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone.
In another aspect, the invention relates to a method of testing the solubility of hydrophobic pharmaceutical agents in a parenteral formulation comprising one or more hydrophobic pharmaceutical agents, that are independently selected from the group consisting of quinazoline-, nitrothiazole-, and indolinone-based compounds; one or more polyoxyhydrocarbyl compounds; and one or more pharmaceutically acceptable surfactants. The method of testing the solubility of the one or more hydrophobic pharmaceutical agents comprises the following steps: (a) interacting the formulation with a hydrophobic support in a first solvent; (b) eluting the hydrophobic pharmaceutical agent from the support with a second solvent; and (c) comparing the amount of the hydrophobic pharmaceutical agent that elutes from the support to the amount that was added to the formulation.
The term xe2x80x9chydrophobic supportxe2x80x9d as used herein refers to a solid matrix that comprises hydrocarbon moieties. The solid matrix can include reverse phase silica, cellulose, and others commonly known to those skilled in the art. The hydrocarbon moieties can include preferably about four carbon atoms, more preferably about eight carbon atoms, and most preferably about eighteen carbon atoms. The solid matrix can be contained within a high performance liquid chromatography (HPLC) column. A pump system attached to such a column can deliver solvents to the matrix at high pressures and render high resolution of compounds eluting from the column.
The term xe2x80x9cinteractingxe2x80x9d as used herein with reference to the solid support refers to adsorbing one or more molecules in a formulation to the solid support. Adsorbing or binding the molecules to the solid support can be accomplished in different solvents, preferably those described herein by example.
The term xe2x80x9celutingxe2x80x9d as used herein with reference to the solid support refers to the processes of desorbing (removing) a hydrophobic pharmaceutical agent such as an indolinone-, a quinazoline-, or a nitrothiazole-based compound adsorbed (reversibly bound) to a solid support. Eluting a compound from a solid support can be accomplished by changing the solvent to one where the hydrophobic pharmaceutical agent no longer binds to the solid support. The second solvent often has a different pH or a different solvent content than the solvent in which the hydrophobic pharmaceutical agent adsorbed to the solid support. When a HPLC column is employed in this process, a hydrophobic pharmaceutical agent is typically bound to the column in one solvent and then eluted by passing another solvent through the column. The hydrophobic pharmaceutical agent flows from the column with the second solvent.
The term xe2x80x9ccomparingxe2x80x9d as used herein in reference to the method of testing the solubility of the hydrophobic pharmaceutical agent refers to difference in the amount of a hydrophobic pharmaceutical agent added to a formulation and the amount of the hydrophobic pharmaceutical agent that is actually dissolved in the formulation. One may determine the amount of the hydrophobic pharmaceutical agent added to the formulation, for example, by weighing the compound before adding it to the formulation. Then one can centrifuge or filter a sample of the formulation to remove any hydrophobic pharmaceutical agent that is not dissolved in the formulation. The filtered or centrifuged formulation can then be injected onto an HPLC column and eluted from it. The concentration of the hydrophobic pharmaceutical agent can then be quantified by techniques commonly known to those skilled in the art, such as by using a ultraviolet detector which measures the amount of an hydrophobic pharmaceutical agent eluted from the column by its absorbance. The concentration of the hydrophobic pharmaceutical agent eluted from the column can be determined from its absorbance and its inherent extinction coefficient and/or by comparing the absorbance to that of standard amounts of the hydrophobic pharmaceutical agent.
In preferred embodiments of the method of testing the solubility of hydrophobic pharmaceutical agents in a parenteral formulation, the parenteral formulation further comprises one or more pharmaceutically acceptable alcohols.
In another aspect, the invention relates to a method of testing the solubility of hydrophobic pharmaceutical agents in an oral formulation comprising one or more hydrophobic pharmaceutical agents that are independently selected from the group consisting of quinazoline-, nitrothiazole-, and indolinone-based compounds; one or more polyoxyhydrocarbyl compounds; one or more polyglycolized lipids; and one or more pharmaceutically acceptable surfactants. The method of testing the solubility of the one or more hydrophobic pharmaceutical agents comprises the following steps: (a) interacting the formulation with a hydrophobic support in a first solvent; (b) eluting the hydrophobic pharmaceutical agent from the support with a second solvent; and (c) comparing the amount of the hydrophobic pharmaceutical agent that elutes from the support to the amount that was added to the formulation.
In preferred embodiments of the method of testing the solubility of hydrophobic pharmaceutical agents in an oral formulation, the parenteral formulation further comprises one or more pharmaceutically acceptable oils.
In preferred embodiments of the method of testing the solubility of hydrophobic pharmaceutical agents, the first solvent comprises phosphate and triethylamine, and the second solvent comprises triethylamine, tetrahydrofuran, and methanol. Preferably the first solvent comprises 0.35 M phosphate and 0.1% triethylamine and the second solvent comprises 0.1% triethylamine, tetrahydrofuran, and methanol mixed in a 40:20:40 ratio.
Most preferably, the hydrophobic pharmaceutical agent is an indolinone-based compound of formula VI.
In yet another aspect, the invention relates to a method of preparing a parenteral formulation. The method comprises the following steps: (a) dissolving one or more hydrophobic pharmaceutical agents into polyoxyhydrocarbyl compounds to form a solution, where the agents are independently selected from the group consisting of: a quinazoline-, a nitrothiazole-, and an indolinone-based compound; (b) dissolving one or more surfactants into the solution; and (c) filtering the solution. In some embodiments, one or more pharmaceutically acceptable alcohols are added to the solution.
In preferred embodiments, the invention relates to the method of preparing a parenteral formulation comprising the following steps: (a) dissolving 0.01 to 10 g/mL PEG-400 into water; (b) dissolving an indolinone-based compound of formula VI into the solution, where R1, R2, R3, and R4 are selected from the group consisting of hydrogen, trihalomethyl, hydroxyl, amine, thioether, cyano, alkoxy, alkyl, amino, bromo, fluoro, chloro, iodo, mercapto, thio, cyanoamido, alkylthio, aryl, heteroaryl, carboxyl, ester, oxo, alkoxycarbonyl, alkenyl, alkoxy, nitro, alkoxyl, and amido moieties; and R5 is an optionally substituted aryl or heteroaryl cyclic moiety; (c) adding 0.01 to 1 g/mL ethanol and 0.001 to 1 g/mL benzyl alcohol to the solution; (d) dissolving 0.01 to 10 g/mL ethoxylated castor oil into the solution; (e) bringing the volume of the solution to about 100 milliliters with distilled water; and (f) filtering the solution through a 0.2 xcexcm nylon filter.
In other preferred embodiments, the invention relates to the method of preparing a parenteral formulation comprising the following steps: (a) dissolving about 35 grams of PEG-400 into water; (b) dissolving about 500 milligrams of an indolinone-based compound of formula VI, where R1, R2, R3, and R4 are selected from the group consisting of hydrogen, trihalomethyl, hydroxyl, amine, thioether, cyano, alkoxy, alkyl, amino, bromo, fluoro, chloro, iodo, mercapto, thio, cyanoamido, alkylthio, aryl, heteroaryl, carboxyl, ester, oxo, alkoxycarbonyl, alkenyl, alkoxy, nitro, alkoxyl, and amido moieties; and R5 is an optionally substituted aryl or heteroaryl cyclic moiety; (c) adding about 11.4 grams of ethanol and 2 grams of benzyl alcohol to the solution; (d) dissolving about 25 grams of CREMOPHOR EL(copyright) into the solution; (e) bringing the volume of the solution to about 100 milliliters with distilled water; and (f) filtering the solution through a 0.2 xcexcm nylon filter.
In yet another aspect, the invention relates to a method of preparing an oral formulation comprising the following steps: (a) melting one or more polyglycolyzed lipids;(b) dissolving one or more polyoxyhydrocarbyl compounds and one or more surfactants, into the melted polyglycolyzed lipid; (c) dissolving one or more hydrophobic pharmaceutical agent into the solution, where the agents are independently selected from the group consisting of a quinazoline-, a nitrothiazole-, and an indolinone-based compound; and (d) filtering the solution. In some embodiments, pharmaceutically acceptable oils are also dissolved into the melted polyglycolyzed lipid.
In preferred embodiments of the methods of making the parenteral and oral formulations, the hydrophobic pharmaceutical agent is an indolinone-based compound of formula VI where R1, R2, R3, and R4 are selected from the group consisting of hydrogen, trihalomethyl, hydroxyl, amine, thioether, cyano, alkoxy, alkyl, amino, bromo, fluoro, chloro, iodo, mercapto, thio, cyanoamido, alkylthio, aryl, heteroaryl, carboxyl, ester, oxo, alkoxycarbonyl, alkenyl, alkoxy, nitro, alkoxyl, and amido moieties; and R5 is an optionally substituted aryl or heteroaryl cyclic moiety.
Preferably, the indolinone-based compound has a structure of formula VI, where R1, R2, R3, and R4 are selected from the group consisting of hydrogen, halogen, alkyl, and alkoxy; and where R5 is a pyrrolyl or thiophenyl moiety optionally substituted with moieties selected from the group consisting of hydrogen, halogen, alkyl, and alkoxy. More preferably, the indolinone-based compound is selected from the group consisting of 3-[(2,4-dimethylpyrrol-5-yl)methylene]-(5-amino)-2-indolinone, 3-[(2,4-dimethylpyrrol-5-yl)methylene]-(5-chloro)-2-indolinone, 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone, and 3-[(3-methylthiophenyl-5-yl)methylene]-(4-methyl)-2-indolinone. In a highly preferred method, the indolinone-based compound is 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone.
The methods of preparing formulations of the invention can be scaled to any volume desired. Thus, even if a method specifies that the total volume of the solution is 100 mL, the formulation can be prepared as a 1 mL sample by proportionally decreasing each component of the formulation by a factor of 100. For example, if 10 grams of PEG-400 is required for a 100 mL volume of the formulation, then a 1 mL sample of the formulation can be prepared by adding only (10 grams)xc3x97(1/100)=0.1 grams of PEG-400.
Dissolving the components of the formulations of the invention can be accomplished by a variety of techniques known to those skilled in the art. These techniques include stirring techniques (manually and with magnetic stirring systems), vortexing techniques, vibration techniques, and sonication techniques. Sonication techniques are typically accomplished using a steel probe that resonates at high frequency vibrations.
In other preferred embodiments, the invention relates to the method of treating or preventing an abnormal condition in a patient in need of such treatment. The method comprises the following steps: (a) diluting a parenteral formulation into a pharmaceutically acceptable solution, said parenteral formulation comprising one or more hydrophobic pharmaceutical agents, that are independently selected from the group consisting of quinazoline-, nitrothiazole-, and indolinone-based compounds; one or more polyoxyhydrocarbyl compounds; and one or more pharmaceutically acceptable surfactants; and (b) parenterally administering the diluted formulation to the patient. In some highly preferred embodiments, the formulation further comprises one or more pharmaceutically acceptable alcohols.
Preferably, the one or more hydrophobic pharmaceutical agents are chosen from a group selected for their positive results in one or more in vitro assays that corresponds to the disease or to the disorder to be treated. Examples of such assays are described in section III of the Detailed Description of the Invention.
In preferred embodiments, the pharmaceutically acceptable solution is selected from the group consisting of saline, 0.45% N saline, WFI (water for injection), D5W (5% dextrose in water), and D5W 0.45% N saline. The ratio of the formulation volume to the pharmaceutically acceptable solution volume is preferably 10:1 to 1:2 (v/v), more preferably 2:1 to 1:3 (v/v), and most preferably 1:1, 1:2, or 1:3 (v/v).
In other preferred embodiments, the invention features a method of treating a patient in need of such treatment using a formulation that comprises: (a) 0.1 to 100 mg/mL of an indolinone-based compound of formula VI, where R1, R2, R3, and R4 are selected from the group consisting of hydrogen, trihalomethyl, hydroxyl, amine, thioether, cyano, alkoxy, alkyl, amino, bromo, fluoro, chloro, iodo, mercapto, thio, cyanoamido, alkylthio, aryl, heteroaryl, carboxyl, ester, oxo, alkoxycarbonyl, alkenyl, alkoxy, nitro, alkoxyl, and amido moieties; and R5 is an optionally substituted aryl or heteroaryl cyclic moiety; (b) 0.01 to 10 g/mL PEG-400; (c) 0.01 to 1 g/mL ethanol; (d) 0.001 to 1 g/mL benzyl alcohol; and (e) 0.01 to 10 g/mL ethoxylated castor oil.
In yet other methods of treatment the formulation comprises: (a) about 5.0 mg/mL of an indolinone-based compound of formula VI, where R1, R2, R3, and R4 are selected from the group consisting of hydrogen, trihalomethyl, hydroxyl, amine, thioether, cyano, alkoxy, alkyl, amino, bromo, fluoro, chloro, iodo, mercapto, thio, cyanoamido, alkylthio, aryl, heteroaryl, carboxyl, ester, oxo, alkoxycarbonyl, alkenyl, alkoxy, nitro, alkoxyl, and amido moieties; and R5 is an optionally substituted aryl or heteroaryl cyclic moiety; (b) about 0.35 g/mL PEG-400; (c)about 0.114 g/mL ethanol; (d) about 0.02 g/mL benzyl alcohol; and (e) about 0.25 g/mL CREMOPHOR EL(copyright).
In a highly preferred embodiment of a method of treatment, the formulation comprises: (a) about 4.5 mg/mL of an indolinone-based compound, 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone; (b) about 45% w/v PEG-400; (c) about 31.5% w/v CREMOPHOR EL(copyright); (d) about 2% w/v benzyl alcohol; and (e) about 9.5% w/v ethanol.
In another aspect, the invention relates to a method of preventing or treating an abnormal condition in a patient in need of treatment comprising the following steps: (a) preparing an acceptable pharmaceutical composition from an oral formulation, said oral formulation comprising: a hydrophobic pharmaceutical agent, one or more polyoxyhydrocarbyl compounds, one or more polyglycolized lipids, and one or more pharmaceutically acceptable surfactants; and (b) administering said composition to said patient. Preferably, the formulation is orally administered. In highly preferable embodiments, the oral formulation further comprises one or more pharmaceutically acceptable oils.
The pharmaceutically acceptable composition is preferably selected from the group comprising: said oral formulation, a hard gelatin capsule filled with said oral formulation, a soft gelatin capsule filled with said oral formulation, and a hard gelatin capsule filled with said oral composition admixed with a granulating agent to form a dry solid composition. In preferred embodiments, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule.
A solid composition of the formulation can be prepared by mixing the formulation in a liquefied state with a pharmaceutically acceptable granulating agent or a mixture of pharmaceutically acceptable granulating agents (for example silicon dioxide, microcrystalline cellulose, starch, calcium carbonate, pectin, crospovidone, polyplasdone and the like).
In preferred embodiments of the method of treatment, the formulation comprises: (a) about 3% w/w of an indolinone-based compound of formula VI, where R1, R2, R3, and R4 are selected from the group consisting of hydrogen, trihalomethyl, hydroxyl, amine, thioether, cyano, alkoxy, alkyl, amino, bromo, fluoro, chloro, iodo, mercapto, thio, cyanoamido, alkylthio, aryl, heteroaryl, carboxyl, ester, oxo, alkoxycarbonyl, alkenyl, alkoxy, nitro, alkoxyl, and amido moieties; and R5 is an optionally substituted aryl or heteroaryl cyclic moiety; (b) about 70% w/w GELUCIRE(copyright) 44/14; (c) about 10% w/w CREMOPHOR EL(copyright); (d) about 10% w/w Miglyol 812; and (e) about 10% w/w polyethylene glycol 600.
In other preferred embodiments of the method of treatment, the formulation comprises: (a) about 3% w/w of an indolinone-based compound of formula VI, where R1, R2, R3, and R4 are selected from the group consisting of hydrogen, trihalomethyl, hydroxyl, amine, thioether, cyano, alkoxy, alkyl, amino, bromo, fluoro, chloro, iodo, mercapto, thio, cyanoamido, alkylthio, aryl, heteroaryl, carboxyl, ester, oxo, alkoxycarbonyl, alkenyl, alkoxy, nitro, alkoxyl, and amido moieties; and R5 is an optionally substituted aryl or heteroaryl cyclic moiety; (b) about 76% w/w LABRASOL(copyright); (c) about 12% w/w CREMOPHOR EL(copyright); and (d) about 12% w/w polyethylene glycol 600.
In yet other preferred embodiments of the method of treatment, the formulation comprises: (a) about 3% w/w of an indolinone-based compound of formula VI, where R1, R2, R3, and R4 are selected from the group consisting of hydrogen, trihalomethyl, hydroxyl, amine, thioether, cyano, alkoxy, alkyl, amino, bromo, fluoro, chloro, iodo, mercapto, thio, cyanoamido, alkylthio, aryl, heteroaryl, carboxyl, ester, oxo, alkoxycarbonyl, alkenyl, alkoxy, nitro, alkoxyl, and amido moieties; and R5 is an optionally substituted aryl or heteroaryl cyclic moiety; (b) about 70% w/w LABRASOL(copyright); (c) about 10% w/w CREMOPHOR EL(copyright); (d) about 10% w/w Miglyol 812; and (e) about 10% w/w polyethylene glycol 600.
In preferred embodiments of the method of treatment, the parenteral or oral formulations comprise an indolinone-based compound having a structure of formula VI, where R1, R2, R3, and R4 are selected from the group consisting of hydrogen, trihalomethyl, hydroxyl, amine, thioether, cyano, alkoxy, alkyl, amino, bromo, fluoro, chloro, iodo, mercapto, thio, cyanoamido, alkylthio, aryl, heteroaryl, carboxyl, ester, oxo, alkoxycarbonyl, alkenyl, alkoxy, nitro, alkoxyl, and amido moieties; and R5 is an optionally substituted aryl or heteroaryl cyclic moiety.
In other preferred embodiments of the method of treatment, the parenteral or oral formulations comprise an indolinone-based compound having a structure of formula VI, where R1, R2, R3, and R4 are selected from the group consisting of hydrogen, halogen, alkyl, and alkoxy; and where R5 is a pyrrolyl or thiophenyl moiety optionally substituted with moieties selected from the group consisting of hydrogen, halogen, alkyl, and alkoxy.
In other preferred embodiments of the method of treatment, the parenteral or oral formulations comprise an indolinone-based compound selected from the group consisting of 3-[(2,4-dimethylpyrrol-5-yl)methylene]-(5-amino)-2-indolinone, 3-[(2,4-dimethylpyrrol-5-yl)methylene]-(5-chloro)-2-indolinone, 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone, and 3-[(3-methylthiophenyl-5-yl)methylene]-(4-methyl)-2-indolinone.
In highly preferred embodiments of the method of treatment, the parenteral or oral formulations comprise the indolinone-based compound, 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone.
In highly preferred embodiments of the invention, the method of treatment is effective in treating or preventing an abnormal condition in a patient, preferably a mammal, more preferably a human, in need of such treatment. Abnormal conditions which may be treated with these formulations are cell proliferative disorders, typically those characterized by abnormal protein kinase activity. Preferably, the formulation inhibits protein kinase activity.
Other features and advantages of the invention will be apparent from the following description of the preferred embodiments and from the claims.